Inflammation is the body's response to tissue damage, including brain tissue after stroke. Stroke is one
of the leading causes of death and disability, affecting more that 795,000 Americans per year. A majority of
strokes are ischemic strokes, where blood flow to the brain is obstructed. Most therapeutic interventions restore
blood flow, but these therapies have a limited time frame in which they are effective. Moreover, some patients
do not improve even with blood flow restoration. One likely explanation for the limited therapeutic benefit of blood
flow restoration after stroke is the secondary damage caused by the acute inflammatory response. This is the
so-called, “ischemia/reperfusion (I/R) injury.” Therefore, further understanding and characterization of the
inflammatory response to stroke is critical to the development of new therapeutic interventions.
Following an ischemic stroke, brain blood vessels respond to inflammatory signals and recruit leukocytes
to the area of damage. Neutrophils (PMN) are the earliest responders to tissue damage in the central nervous
system (CNS). Like other leukocytes, PMN interact with adhesion molecules on the endothelial cell surface and
undergo transendothelial migration (TEM), squeezing between endothelial cells and migrating into the tissue bed.
TEM is important because it is essentially irreversible, committing the cell to extravasation.
Our research shows inhibition of TEM significantly reduces stroke infarct size in acute stroke, however
the mechanism connecting TEM blockade to a reduction in infarct size is unknown. We show that blocking TEM
alters the spatiotemporal distribution of leukocyte infiltration and extravasation across the ischemic core and
penumbra but does not change the total number of leukocytes recruited to infarcted region. Analysis of the
leukocyte composition showed PMN are the major infiltrating leukocyte type in acute stroke. These findings
suggest that modulating PMN infiltration pattern rather than reducing total leukocyte recruitment may have a
protective effect in stroke. We seek to understand the mechanisms by which myeloid cell TEM blockade results
in reduced stroke infarct size and the effect of specifically interfering with PMN extravasation on stroke outcomes.
To understand effect of TEM blockade following I/R, our first aim will identify how inhibition of TEM during
I/R injury in acute stroke alters the immune landscape of the stroke microenvironment. Our studies will identify
differences between in leukocyte types over time across ischemic brain regions and differences in the cytokine
profile due to TEM blockade. Our second aim will determine the therapeutic effect of blocking leukocyte
extravasation in comparison to selective PMN depletion following I/R. Our studies will be conducted at different
time points after reperfusion, identifying the effect of inhibition on brain pathology, and mouse motor function.
PMN extravasation will be inhibited through two methods: use of TEM-blocking antibodies and the selective
depletion of PMN. Completion of these studies will provide insight into the mechanisms regulating PMN response
to I/R injury and potentially identify a therapeutic intervention that can be used at the relevant time frame.